Zika Virus Targets Glioblastoma Stem Cells through a SOX2-Integrin αvβ5 Axis

Zhe Zhu, Pinar Mesci, Jean A. Bernatchez, Ryan C. Gimple, Xiuxing Wang, Simon T. Schafer, Hiromi I. Wettersten, Sungjun Beck, Alex E. Clark, Qiulian Wu, Briana C. Prager, Leo J.Y. Kim, Rekha Dhanwani, Sonia Sharma, Alexandra Garancher, Sara M. Weis, Stephen C. Mack, Priscilla D. Negraes, Cleber A. Trujillo, Luiz O. PenalvaJing Feng, Zhou Lan, Rong Zhang, Alex W. Wessel, Sanjay Dhawan, Michael S. Diamond, Clark C. Chen, Robert J. Wechsler-Reya, Fred H. Gage, Hongzhen Hu, Jair L. Siqueira-Neto, Alysson R. Muotri, David A. Cheresh, Jeremy N. Rich

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Zika virus (ZIKV) causes microcephaly by killing neural precursor cells (NPCs) and other brain cells. ZIKV also displays therapeutic oncolytic activity against glioblastoma (GBM) stem cells (GSCs). Here we demonstrate that ZIKV preferentially infected and killed GSCs and stem-like cells in medulloblastoma and ependymoma in a SOX2-dependent manner. Targeting SOX2 severely attenuated ZIKV infection, in contrast to AXL. As mechanisms of SOX2-mediated ZIKV infection, we identified inverse expression of antiviral interferon response genes (ISGs) and positive correlation with integrin αv (ITGAV). ZIKV infection was disrupted by genetic targeting of ITGAV or its binding partner ITGB5 and by an antibody specific for integrin αvβ5. ZIKV selectively eliminated GSCs from species-matched human mature cerebral organoids and GBM surgical specimens, which was reversed by integrin αvβ5 inhibition. Collectively, our studies identify integrin αvβ5 as a functional cancer stem cell marker essential for GBM maintenance and ZIKV infection, providing potential brain tumor therapy.

Original languageEnglish (US)
Pages (from-to)187-204.e10
JournalCell Stem Cell
Volume26
Issue number2
DOIs
StatePublished - Feb 6 2020

Bibliographical note

Funding Information:
We thank Drs. Peter Yingxiao Wang and Hsin-Hung Lin (UC, San Diego) for the PGK-EGFP lentiviral vector and Dr. Elsa Molina (UC, San Diego Stem Cell Genomics Core) for technical assistance with experiments using the NanoString nCounter Sprint. We also acknowledge access and use of the UCSD Screening Core to perform part of the experiments presented in this manuscript. This work was made possible in part by CIRM Major Facilities grant FA1-00607 (to the Sanford Consortium for Regenerative Medicine). P.M. has an International Rett Syndrome Foundation (IRSF) mentored training fellowship. A.R.M. is supported by the California Institute for Regenerative Medicine (DISC2-09649). These studies were supported by the NIH through CA217065 (to R.C.G.); CA217066 (to B.C.P.); CA203101 (to L.J.Y.K.); CA159859 and CA199376 (to S.S.); NS097649-01 and CA240953-01 (to C.C.C.); NS096368 (to R.J.W.-R.); R01DK103901 and R01AA027065 (to H.H.); MH107367 and N5105969 (to A.R.M.); CA045726 and CA050286 (to D.A.C.); and CA197718, CA154130, CA169117, CA171652, NS087913, and NS089272 (to J.N.R.). Z.Z. P.M. J.L.S.-N. D.A.C. A.R.M. and J.N.R. designed the experiments, analyzed the data, and wrote the manuscript with contributions from all authors. Z.Z. P.M. J.A.B. S.T.S. R.C.G. X.W. H.I.W. S.B. A.E.C. Q.W. B.C.P. L.J.Y.K. Z.L. J.F. R.Z. A.W.W. and R.D. performed the experiments. S.T.S. R.C.G. B.C.P. and L.J.Y.K. performed database analyses. S.S. S.D. C.C.C. R.J.W.-R. F.H.G. J.D.S.-N. M.S.D. and H.H. provided scientific input and helped edit the manuscript. A.G. S.M.W. S.C.M. P.D.N. C.A.T. L.O.P. R.J.W.-R. and J.L.S.-N. provided key reagents. A.R.M. is a co-founder and has equity interest in TISMOO, a company dedicated to genetic analysis focusing on therapeutic applications customized for autism spectrum disorder and other neurological disorder origin genetics. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. D.A.C. is the co-founder of TargeGen. D.A.C. is a founder of a new company, AlphaBeta Therapeutics, that is developing an antibody to integrin alphaVbeta3, involved in cancer treatment; however, this company is not yet funded. M.S.D. is a consultant for Inbios and Atreca and on the Scientific Advisory Board of Moderna.

Funding Information:
We thank Drs. Peter Yingxiao Wang and Hsin-Hung Lin (UC, San Diego) for the PGK-EGFP lentiviral vector and Dr. Elsa Molina (UC, San Diego Stem Cell Genomics Core) for technical assistance with experiments using the NanoString nCounter Sprint. We also acknowledge access and use of the UCSD Screening Core to perform part of the experiments presented in this manuscript. This work was made possible in part by CIRM Major Facilities grant FA1-00607 (to the Sanford Consortium for Regenerative Medicine). P.M. has an International Rett Syndrome Foundation (IRSF) mentored training fellowship. A.R.M. is supported by the California Institute for Regenerative Medicine ( DISC2-09649 ). These studies were supported by the NIH through CA217065 (to R.C.G.); CA217066 (to B.C.P.); CA203101 (to L.J.Y.K.); CA159859 and CA199376 (to S.S.); NS097649-01 and CA240953-01 (to C.C.C.); NS096368 (to R.J.W.-R.); R01DK103901 and R01AA027065 (to H.H.); MH107367 and N5105969 (to A.R.M.); CA045726 and CA050286 (to D.A.C.); and CA197718 , CA154130 , CA169117 , CA171652 , NS087913 , and NS089272 (to J.N.R.).

Publisher Copyright:
© 2019 Elsevier Inc.

Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.

Keywords

  • Integrin αvβ5
  • Sox2
  • Zika
  • cancer stem cell
  • glioblastoma
  • glioblastoma stem cell
  • glioma
  • interferon
  • oncolytic virus
  • organoid

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